Retinopathy of Prematurity

Author: Ameen Marashi, MD

History

Calculating and documenting the gestational, postmenstrual, and chronological age in collaboration with neonatologist is essential to initiate the fundus exam in the appropriate time, as neonates with gestational age 30 weeks and less are at risk of developing ROP.

Documenting the weight of the neonate is essential as premature babies with weight 1500g and less are more prone to develop retinopathy of prematurity (ROP).

It is essential to collect data about oxygenation, and its saturation as the biphasic oxygen protocol is associated with less ROP and need of treatment when compared to static target oxygen without an increase in mortality [1].

A collaboration with neonatologist is essential to document cardiorespiratory or gastrointestinal associated disorders or other diseases believed by neonatologist that may increase the risk of developing ROP, especially for infants between weight 1500 and 2000 g and with gestational age 30 weeks and more.

If the infant was referred from another center, a communication established with both caring ophthalmologist and neonatologist to obtain a detailed report about follow-up findings and previous treatment procedures details.

A list of ocular examination should set

1. Conjunctival examination to rule out inflammation along with a corneal examination to check its clarity.

2. Iris exam to rule out of rubeosis iridis.

3. Pupil exam to check reactivity.

4. Check the red reflex.

5. A Bilateral dilated fundus exam with indirect ophthalmoscopy using 28D lens after placing sterile pediatric speculum to reduce cross-contamination and using a sterile indenter to rotate the eye and indent the sclera to see retinal periphery documenting:

· The maturity of retinal vessels

· The presence of demarcation line which is a feature of stage one or ridge which is a feature of stage two

· The presence of neovascular proliferation on the ridge, which resembles stage three of ROP and appears as a ridge with pinkish to red color and shouldn’t be mistaken with retinal detachment.

· Presence of vascular dilatation and tortuosity as Plus disease defined as vascular dilatation and tortuosity in two quadrants

· The location of retinal findings documented as zone I defined as a circle with the optic disc being the center with a radius twice the distance between the optic disc and the center of the macula where zone II extends from the border of zone I to Ora Serrata in the nasal retina while to anatomical equator in the temporal retina while the remaining temporal crescent is zone III.

· The presence of total or subtotal retinal detachment and the status of macula if it is detached or not or any dragging of the macula or fibrin formation are documented as well.

· Preretinal hemorrhage occur due to birth and should be documented as well.

ROP assessment

When screening infants for ROP, the examiner should assess precisely the following:

Zone of ROP: assessment of ROP location is essential as the treatment and follow-up are different between zones (figure 1).

Stage: documentation and assessment of ROP stage can help to determine initiation of treatment and to plan follow up as stage one shows demarcation line between the vascularized and non-vascularized retina, as ROP progresses this demarcation line turns into a ridge which is a feature of stage two when the ridge presented with neovascular proliferation with pinkish color then it is stage three. However, stage four is presented with subtotal detachment with macula on (4a) or macula off (4b), in contrast, total retinal detachment is a feature of stage 5.

Presence of Plus disease: Examiner should search for the presence or absence of tortuosity and dilatation of retinal vessels as the presence of tortuosity and dilatation in one quadrant, then it is preplus disease where presence vascular tortuosity and dilatation in two quadrants refer to Plus disease. However, if the examiner is not sure that it is a Plus disease or not, then a review of previous fundus images if there is a ROP progression or if ROP progressed within one or two weeks, then it is a Plus disease.

Category

No ROP is cases of immature vascularization as the retina is completely vascularized until 40 weeks of gestation,

Mild ROP is the absence of Plus disease with stage one or two in zone II or any stage in zone III categorized.

Type two ROP (prethreshold disease) is the absence of Plus disease with stage one or two in the zone I or stage three in zone II

Type one ROP (threshold disease) categorized as Plus disease with any stage in the zone I, stage 3 without Plus disease in the zone I or stage two or three with Plus disease in zone II.

Aggressive posterior AP-ROP which is a severe form with a high risk of ROP progression, defined as a posterior location of ROP with prominent Plus disease and ill-defined nature of retinopathy (difficult to differentiate between arterioles and venules and to identify demarcation line).

Diagnostic tests


Fundus images

It is an essential ancillary test for ROP screening as it has a huge value for diagnosing the precise zone of ROP changes and hence helps in monitoring the treatment efficacy and follow-up.

Examining neonates is hard and needs a lot of experience, which makes it sometimes hard to determine if the ROP changes are in the zone I or II and in what stage, so fundus imaging is helpful to locate these ROP changes precisely.

Following up with the fundus image makes it clear if the treatment is effective, under-treated (skip or non-treated areas), or over-treated and to assess the regression of ROP and post-treatment.

There are several ways to obtain fundus images for ROP neonates:

Retcam3, which is a contact handheld fundus camera that can capture wide-field images up to 130 degrees when placed on the surface of the cornea with a coupling solution and topical anesthesia, can capture still images with video recording and an inbuilt software that can provide a comparison between follow-up sessions.

There are other commercially available wide-field cameras such as PanoCam, 3NETHRA NEO, and ICON by Phoenix

Another wide-field modality is by OPTOS [2], which has a field of view of up to 200 degrees, but the neonate needs to be sedated and positioned appropriately for fundus image capturing.

Pictor by VOLK Is a portable and non-contact device but has a narrow field of view of up to 40 degrees, but it is useful for outpatient neonates [3].

All the modalities mentioned above for ROP screening are expensive; however, a cost-effective solution for ROP screening is to use the mobile camera with a flash in video mode and 28D lens to capture, and then still images can be reproduced later and saved in the mobile and then transferred to a computer for storage and follow-up.

However, this technique is not easy to do with a single person. However, a MIIRetCam [4] (or any other similar devices) may provide a better solution which fixates the mobile and 28D lens in the proper distance required to focus the retinal image on the mobile and make the process much more comfortable.


Fundus Fluorescein Angiography (FFA)

Retcam3, along with Panocam and OPTOS are capable of capturing FFA images; the fluorescein dose is 0.08-0.1 ml/kg injected I.V., FFA performed under general anesthesia after taking several colored images [5].

FFA can determine the presence of active proliferation, which features as leak and precisely delineate ischemic and non-ischemic areas, which are very useful to determine the stage, location, and progression of ROP [6].

FFA is handy to determine the presence of under treatment (incomplete laser photocoagulation), or over treatment (Laser burns extends over the ridge), especially for cases of zone II treated with laser and needs follow-up to assess treatment efficacy [7].

FFA may determine retinal fold in cases of the detached retina, which may feature a fibrovascular membrane forms from the ridge to retinal periphery and may be useful to assess whether the macula is on or off in certain situations.


Timing of examination for detecting prethreshold ROP

The optimum age for the examination should be calculated on postmenstrual age which is a sum of gestational age plus chronological age; the optimum timing is about 31 weeks postmenstrual age for cases with gestational age 25 to 27 however for neonates with gestational age between 28 and 30 weeks are scheduled for examination within four weeks [8].

Infants born before 25 weeks of age are usually examined within six weeks despite the recommendations by CRYO-ROP study for examination on 31 weeks of gestational age (table one) to identify aggressive ROP as early as possible, especially in high-risk infants.

Table one The schedule for detecting prethreshold ROP before requiring treatment [9]

Treatment options

Intravitreal Anti-VEGF

Intravitreal injection of Anti-VEGF, such as Bevacizumab, is effective in treating ROP, especially in cases of ROP stage three with Plus disease in the zone I [10] as it may offer safer with better anatomical and functional results than laser treatment [11].

Anti-VEGF can utilize whenever laser treatment is not possible even in ROP zone II, especially in cases with non-clear media, laser not available, or there is not enough experience to treat with laser. Anti-VEGF can be combined with laser treatment or used in cases of ROP persists despite laser treatment [13]. Anti-VEGF may offer better short-term anatomical results than laser in cases of type 1 ROP treated before 36 weeks postmenstrual age [32] .

Two Anti-VEGF agents used to treat ROP, Ranibizumab 0.25 mg (0.025 ml) [12] or Bevacizumab 0.25mg (0.01 ml) [14]. However, Ranibizumab seems to be safer than Bevacizumab. Still, it is more expansive and needs frequent injection as recurrence may occur within eight weeks [15] in contrast to Bevacizumab, which is much cheaper, and recurrence may occur within 16 weeks [16].

Injection technique

Injection carried out bilateral (In cases of bilateral ROP threshold disease) under general anesthesia (It can also be done under topical anesthesia in more expert hands) using a microscope with dilated pupils to see the needle and medication injected.

The injection should be carried out in sterile conditions where the injection site is prepared by disinfecting the skin using povidone-iodine 10% and the conjunctiva using povidone-iodine 4%. The injection is carried out after placing sterile drape and lid speculum isolating eyelashes.

Injection site measured with calipers 1 to 1.5 mm from the limbus, the injection carried out with 30 gauge needle and should penetrate about 4 mm only perpendicular to the sclera toward the optic nerve [17], care must be taken to avoid touching the lens as the lens of the neonate is thick.

The infant followed up the next day to do a retinal examination to rule out tractional retinal detachment. Endophthalmitis is ruled out within 2-4 days. Fundus exam carried out weekly as in the first week ROP should be stable or slightly better in case of worsening. Examination repeated within three days (post the first week) if worsening persists then treated promptly with intravitreal Anti-VEGF is used in a posterior disease in cases of a low dose of AntiVEGF are used initially. However, in cases that are not a posterior disease, the laser can be considered for retreatment.

Within the second week, follow up with successful intravitreal Anti-VEGF treatment, ROP should be regressed [18].

Laser

Laser treatment for ROP is most effective in cases of ROP with threshold disease in zone II [19], as applying the laser to zone I may cause macular dragging [20]; however, the laser requires skill and training to apply burns sufficiently.

Laser applied in one session with medium white intensity covering all ischemic areas anterior to the ridge without leaving skip areas of treatment, as skip areas may induce treatment failure and progression of ROP.

The Laser can be combined with intravitreal Anti-VEGF in cases of treatment failure, or ROP regressed to zone II [21].

Laser technique

The most used laser for ROP treatment is an infrared or red laser as using green, or yellow laser is possible but may cause laser uptake on the crystalline lens because of the presence of tunica vasculosa lentis.

Laser performed using laser indirect ophthalmoscopy with 28 D diopter lens in dilated pupils under sedation, then placing a sterile lid speculum to have adequate exposure and scleral indenter to permit peripheral retinal view up to Ora Serrata for laser application.

Laser initiated in the temporal ischemic area from the Ora Serrata to the ridge by applying laser burns spaced almost one burn apart, then applied to ischemic areas 360 degrees with cautious laser application in superior, inferior, and nasal retina as ischemic areas become thinner and unnecessary laser burns in non-ischemic retina avoided in order not to induce complications, this best achieved by placing the scleral indenter on the limbus and slowly move toward the equator from one area to another.

After treatment is completed in 360 degrees, an inspection is carried out to see if there are skip areas and should be treated promptly as skip areas may induce treatment failure [22].

A dexamethasone 1mg/ml b.i.d. and Atropine 0.1% b.i.d. prescribed for two weeks, but neonate followed up weekly as in the first week ROP should be stable or not worse, in case of worsening, then examination repeated to rule out skip areas (should be treated promptly). If there are no skip areas, then exam repeated under general anesthesia within three days to inspect for skip areas again and treated promptly with intravitreal Anti-VEGF.Within the second week, follow-up in successful laser treatment, laser scars form, and ROP regressed.

Vitrectomy

Lens sparing pars plana vitrectomy is required in cases of stage 4 with subtotal retinal detachment; however, in cases of ROP stage 5 with total retinal detachment, pars plana vitrectomy may improve anatomical outcome without improvement of visual function.

Vitrectomy technique

Lens sparing pars plana vitrectomy preferred, but If lens salvaging is not possible, then lensectomy carried out with the increased risk of amblyopia development.

When inserting the infusion cannula, it is essential to make sure that it is in the vitreous cavity and not blocked by the lens and thus may induce choroidal detachment.

Only core vitrectomy performed with limited peripheral core vitrectomy required up to the equator, limited posterior vitreous detachment (PVD) induction may be attempted gently [24] but do not insist on inducing PVD as it may induce retinal tears and retinal detachment, which may lead to blindness, usually by the end of vitrectomy, intravitreal Anti-VEGF injected using an adult dose.

Consider removing posterior vitreous in the case of posterior hyaloid contraction syndrome [22].

In cases that a fibrovascular membrane extends from the peripheral retina to the lens, removal of those membranes is done either by vitrector or by knife [22].

Management of retinopathy of prematurity (ROP)

Recommendation for ROP in zone I

-In cases of stage one or two without Plus disease (Type-two ROP), regressing ROP or immature retinal vascularization a weekly or less follow up warranted and in case of ROP stage one or two progressed to Plus disease or to stage three then treatment with intravitreal injection of Anti-VEGF recommended [23] with weekly follow up if ROP didn’t improve or worsened within one-week laser treatment with or without intravitreal injection repeated within three days; within the second week follow up with successful intravitreal Anti-VEGF treatment, ROP should be regressed.

- In case of stage one, two, and three with Plus disease or stage three without Plus disease (Type-one ROP) treatment with intravitreal injection of Anti-VEGF recommended with weekly follow up, if ROP didn’t improve or worsened within one week, treat with a laser with or without intravitreal injection repeated within three days; within the second week follow up with successful intravitreal Anti-VEGF treatment, ROP should be regressed.

- In case ROP recurs after successful intravitreal Anti-VEGF injection, then an intravitreal Anti-VEGF injection is repeated.

- In case that ROP fails to regress, then laser treatment may be added with or without additional intravitreal Anti-VEGF then weekly follow up [25].

- In case that intravitreal Anti-VEGF treatment is not possible or not available, then laser treatment is recommended [29].

- In case ROP progressed to stage four, then it should be managed as stage 4 (explained later in the text), or ROP regressed to zone II then it managed as ROP zone II (See next paragraph).


Recommendation for ROP in zone II

- In case of stage one without Plus disease (mild ROP) or regressing ROP follow up recommended every two weeks but if stage one progressed to stage two or three with Plus disease (Type-one ROP) then treatment with laser recommended then followed up weekly as in the first week ROP should be stable or not worse, in case of worsening then examination repeated to rule out skip areas (should be treated promptly) if there are no skip areas then exam repeated under general anesthesia within three days to inspect for skip areas again and treated promptly with intravitreal Anti-VEGF [28]; within the second week follow up in successful laser treatment laser scars form and ROP regressed.

- In case of ROP stage two (mild ROP) then one to two weeks follow up or ROP stage three without Plus disease (Type-two ROP) then weekly follow up if ROP progressed to Plus disease (Type-one ROP) then treatment with laser recommended then followed up weekly, as in the first week ROP should be stable or not worse, in case of worsening then examination repeated to rule out skip areas (should be treated promptly) if there are no skip areas then exam repeated under general anesthesia within three days to inspect for skip areas again and treated promptly with intravitreal Anti-VEGF; within second week follow up in successful laser treatment laser scars form and ROP regressed.

-In case of ROP stage two or three with Plus disease (Type-one ROP) then treatment with laser recommended then followed up weekly as in the first week ROP should be stable or not worse, in case of worsening then examination repeated to rule out skip areas (should be treated promptly) if there are no skip areas then exam repeated under general anesthesia within three days to inspect skip areas again and treated promptly with intravitreal Anti-VEGF; within second week follow up in successful laser treatment laser scars form and ROP regressed.

- In the case of ROP recur after successful treatment with laser, then intravitreal Anti-VEGF recommended and weekly followed up.

- In case that laser treatment is not possible or not available, then intravitreal Anti-VEGF injection recommended [28].

- In case ROP progressed to stage four, then it should be managed as stage 4 (explained later in the text), or ROP regressed to zone III, then it managed as ROP zone III (See next paragraph).

Recommendation for ROP in zone III

In the case of stage one, two or three without Plus disease (mild ROP) or regressing ROP, then follow up every three weeks recommended.

Recommendation for ROP stage 4

In cases of subtotal detachments, an urgent lens sparing vitrectomy recommended laser can be added before surgery if possible. Still, the mainstay management is pars plana vitrectomy without lensectomy if possible; Anti-VEGF avoided in stage 4 if the surgery is delayed for more than 48 hrs [24].

Recommendation for ROP stage 5

Although pars plana vitrectomy may improve, anatomical outcome visual prognosis is poor [30].

Flow chart summarizes the approach and management of retinopathy of prematurity

Follow up and prognosis

- When treating type one ROP with laser, regression occurs within two weeks post-treatment, but a weekly follow up recommended, in case of ROP didn’t improve or worsening within the first week then revaluation carried out under general anesthesia to inspect skip areas, and more laser added to skip areas, then reassess within three days if not better then add intravitreal Anti-VEGF.

- When treating Type-one ROP with Anti-VEGF, regression occurs within two weeks, but a weekly follow up recommended, in case of ROP, didn’t improve or worsening within the first week, then laser added with or without intravitreal injection of Anti-VEGF scheduled within three days.

- In case ROP recurs after successful intravitreal Anti VEGF injection, then an intravitreal Anti-VEGF injection repeated, care must be taken that infants treated with intravitreal Anti-VEGF warranted for scheduled follow up for many years, as a late proliferative activation may occur [26].

-Laser, intravitreal Ranibizumab, and intravitreal Bevacizumab effectively treated ROP type one. Still, the recurrence can occur within 50 weeks postmenstrual age when treated with intravitreal Ranibizumab (20.8%) and intravitreal Bevacizumab (10%) postmenstrual and earlier laser (18%). Therefore, a long-term follow-up is required, especially in initial treatment cases with early postmenstrual age, low Apgar score, multiple births, and ROP zone one [31].

-In cases of ROP zone I, Follow up stopped when ROP regressed; full vascularization occurs 360° up to ora Serrata or after 50 weeks of menstrual age and no pretherhold disease.

-In cases of ROP zone II Follow up stopped when ROP regressed, or after 50 weeks of menstrual age and no pretherhold disease.

-In cases of ROP zone III Follow up stopped when full vascularization occurs in zone III, 360° up to ora Serrata, or after 50 weeks of menstrual age.

Acknowledgments

Special thanks to S.Ozdek, U.Spandau, N.Refika, and A.Refai for their help in editing this section

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These guidelines were reviewed and updated in January 2021